Pain perception, or nociception, is mediated by the peripheral terminals of a group of specialized sensory neurons, termed nociceptors. A wide variety of physical and chemical stimuli induce activation of such neurons in mammals, leading to recognition of a potentially harmful stimulus. Inappropriate or excessive activation of nociceptors, however, can result in debilitating acute or chronic pain.
Generally pain is experienced when the free nerve endings which constitute the pain receptors in the skin as well as in certain internal tissues are subjected to mechanical, thermal, chemical or other noxious stimuli. The pain receptors can transmit signals along afferent neurons into the central nervous system and thence to the brain.
The causes of pain can include inflammation, physical injury, infectious disease, chemical or anoxic injury, muscle spasm and the onset of a neuropathic event or syndrome. Ineffectively treated pain can be devastating to the person experiencing it by limiting function, reducing mobility, complicating sleep, and dramatically interfering with the quality of life.
Inflammation is a physiological condition characterized in the acute form by the classical signs of pain, heat, redness, swelling and loss of function. Inflammatory pain can occur when tissue is damaged. For example, physical, chemical, and thermal events, surgery, infection and autoimmune diseases can cause tissue damage and inflammation. When a tissue is damaged, a host of endogenous pain-inducing substances, for example bradykinin and histamine can be released from the injured tissue. The pain-inducing substances can bind to receptors on the sensory nerve terminals and thereby initiate afferent pain signals.
Additionally, pain-inducing substances can be released from nociceptive afferent terminals, and neuropeptides released from sensory terminals can accentuate an inflammatory response. Thus, during inflammation there can be a sprouting of peptidergic peripheral fibers and an increased content of peptide, with many fibers showing a coexistence of substance P (SP) and calcitonin gene related peptide (CGRP). Substance P can induce contraction of endothelia cells, which in turn causes plasma extravasation to allow other substances (bradykinin, AIP, histamine) to gain access to the cite of injury and the afferent nerve terminals. Substance P release by the sensory nerve terminal can also degranulate mast cells. This process is thought to be an important factor in neurogenic inflammation due to the release of inflammatory mediators such as histamine and serotonin and the release of proteolytic enzymes which catalyze the production of bradykinin. CGRP apparently does not produce plasma extravasation, but is a powerful vasodilator and also acts synergistically with SP and other inflammatory mediators to enhance plasma extravasation. All the above listed inflammatory mediators can either sensitize nociceptors or produce pain. Hence, inhibition of the inflammatory mediators' release and/or activity can be useful in the treatment of common inflammatory diseases such as, for example, asthma, arthritis, dermatitis, rhinitis, cystitis, gingivitis, thrombo-phlelitis, glaucoma, astro-intestinal diseases or migraine.
Although inflammatory pain is generally reversible and subsides when the injured tissue has been repaired or the pain inducing stimulus removed, present methods for treating chronic inflammatory pain have many drawbacks and deficiencies. Thus, the typical oral, parenteral or topical administration of an analgesic drug to treat the symptoms of pain, for example, an antibiotic to treat inflammatory pain causing factors, can result in widespread systemic distribution of the drug and undesirable side effects. Additionally, current therapy for inflammatory pain suffers from short duration of drug efficacy, which necessitates frequent drug re-administration with possible resulting increasing drug tolerance and resistance, antibody development and/or drug dependence and addiction, all of which are unsatisfactory. Furthermore, frequent drug administration increases the expense of the regimen to the patient and can require the patient to remember to adhere to a dosing schedule.
Examples of treatments for inflammation and muscle pain include non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen; and opioids, such as morphine.
NSAIDs alleviate pain by inhibiting the production of prostaglandins released by damaged tissues. Prostaglandins have been shown to be peripheral mediators of pain and inflammation, as in arthritic diseases, and a reduction in their concentration provides relief to patients. It has been suggested that prostaglandins are involved in the mediation of pain in the spinal cord and the brain, which may explain the analgesic effects of NSAIDS in some pain states that do not involve inflammation or peripheral tissue damage. However, prostaglandins are only one of several mediators of pain. As such, NSAIDs have a ceiling of activity above which increasing doses do not give more pain relief.
Furthermore, NSAIDs have side effects that limit their usefulness. For example, they can cause irritation of the gastrointestinal tract and prolonged use may lead to the development of extensive ulceration of the gut. This is particularly true in elderly patients who frequently use NSAIDs for their arthritis conditions.
The therapeutic actions of opioids are on the central nervous system including the brain and spinal cord. Opioids inhibit the efficiency of neurotransmission between the primary sensory afferents (principally C-fibers) and the projection neurons. They achieve this by causing a prolonged hyperpolarization of both elements of these synapses. The use of opioids is effective in alleviating most types of acute pain and chronic pain caused by the malignant tumors. There are, however, a number of chronic malignant pain conditions that are partly or completely refractory to opioid analgesia, particularly those that involve nerve compression, e.g. by tumor formation and growth. Unfortunately opioids also have unwanted side-effects including depression of the respiratory system, constipation, and psychoactive effects including sedation, euphoria and drug dependency. These side effects occur at doses similar to those that produce analgesia and, therefore, limit the doses that can be given to patients. Additionally, opioids such as morphine and heroin are well-known drugs of abuse that often lead to rapid increase in drug tolerance and physical dependence. With the development of tolerance, the dose and frequency of drug required to produce the same analgesic effect increases with time. This may lead to a condition in which the doses required to alleviate the chronic unremitting pain can be life-threatening due to previously mentioned side-effects. As used herein, the term “chronic” means pain lasting for one month duration or longer. “Acute pain” is defined as pain of shorter duration than chronic pain and of high intensity.
Although pain arising from inflammation and muscle spasm can be initiated by mechanical or chemical stimulation of the primary sensory neuron free terminal, neuropathic pain does not require an initial stimulus to the peripheral, free nerve terminal. Neuropathic pain is a persistent or chronic pain syndrome that can result from damage to the nervous system, the peripheral nerves, the dorsal root ganglion, dorsal root, or to the central nervous system.
Neuropathic pain involves pain signal transmission in the absence of stimulus, and typically results from damage to the nervous system. In most instances, such pain is thought to occur because of sensitization in the peripheral and central nervous systems following initial damage to the peripheral system (e.g., via direct injury or systemic disease). Neuropathic pain is typically burning, shooting and unrelenting in its intensity and can sometimes be more debilitating that the initial injury or disease process that induced it.
Existing treatments for neuropathic pain are largely ineffective. Opiates, such as morphine, are potent analgesics, but their usefulness is limited because of adverse side effects mentioned earlier, such as rapid development of drug tolerance, physical addictiveness and withdrawal properties, as well as respiratory depression, mental status changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting, and alterations in the endocrine and autonomic nervous systems. In addition, neuropathic pain is frequently non-responsive or only partially responsive to conventional opioid analgesic regimens. Treatments employing the N-methyl-D-aspartate antagonist ketamine or the alpha(2)-adrenergic agonist clonidine can reduce acute or chronic pain, and permit a reduction in opioid consumption, but these agents are often poorly tolerated due to significant side effects.
Neuropathic pain syndromes include allodynia, various neuralgias such as post herpetic neuralgia and trigeminal neuralgia, phantom pain, and complex regional pain syndromes, such as reflex sympathetic dystrophy and causalgia. Causalgia is often characterized by spontaneous burning pain combined with hyperalgesia and allodynia.
Unfortunately, there is no existing method for adequately, predictably and specifically treating established neuropathic pain (Woolf C. et al., Neuropathic Pain: A etiology, Symptoms, Mechanisms, and Management, Lancet 1999; 353: 1959-64) as present treatment methods for neuropathic pain consists of merely trying to help the patient cope through psychological or occupational therapy, rather than by reducing or eliminating the pain experienced.
Therefore, there remains a need for an improved method or compound for the treatment of unremitting chronic and acute pain, including inflammatory pain. There is also a need for improved methods and agents for treatment of immunological and autoimmune diseases and conditions. This is achieved by administration of arsenic compounds, in accordance with this disclosure.